Pregled bibliografske jedinice broj: 1101635
Computational insight into the catalytic activity of monoamine oxidase enzyme for targeting neurological diseases
Computational insight into the catalytic activity of monoamine oxidase enzyme for targeting neurological diseases // Book of Abstracts of the 10th Joint Meeting on Medicinal Chemistry / Basarić, Nikola ; Namjesnik, Danijel ; Perković, Ivana ; Stepanić, Višnja (ur.).
Zagreb: Hrvatsko kemijsko društvo, 2017. str. 55-55 (plenarno, međunarodna recenzija, sažetak, znanstveni)
CROSBI ID: 1101635 Za ispravke kontaktirajte CROSBI podršku putem web obrasca
Naslov
Computational insight into the catalytic activity
of monoamine oxidase enzyme for targeting
neurological diseases
Autori
Vianello, Robert
Vrsta, podvrsta i kategorija rada
Sažeci sa skupova, sažetak, znanstveni
Izvornik
Book of Abstracts of the 10th Joint Meeting on Medicinal Chemistry
/ Basarić, Nikola ; Namjesnik, Danijel ; Perković, Ivana ; Stepanić, Višnja - Zagreb : Hrvatsko kemijsko društvo, 2017, 55-55
ISBN
978-953-55232-8-4
Skup
10th Joint Meeting on Medicinal Chemistry
Mjesto i datum
Dubrovnik, Hrvatska, 25.06.2017. - 28.06.2017
Vrsta sudjelovanja
Plenarno
Vrsta recenzije
Međunarodna recenzija
Ključne riječi
monoamine oxidase enzyme
Sažetak
Monoamine oxidase (MAO) is an FAD-dependent flavoenzyme responsible for metabolizing a very broad range of biogenic and dietary amines including many neurotransmitters in the brain, such as dopamine and serotonin, whose imbalance is extensively linked with the development and progression of many neurological disorders. That is why MAO has been a central pharmacological target in treating neurodegeneration for over 60 years. Still, despite decades of extensive research, neither its catalytic nor inhibition mechanisms have yet been clearly determined, which is of paramount importance in designing novel and effective MAO inhibitors as transition state analogues, particularly since current drugs show serious adverse effects and tend to address only the symptoms rather than the cause of the dysfunction. On the basis of QM calculations and EVB QM/MM simulations, we have proposed a new two-step hydride mechanism for the MAO catalysis (Figure 1), [2] which is gaining some affirmation in the literature, [3] and is fully corroborated by a very recent 13C kinetic isotope effect measurements.[3c] Calculations of the pKa values of three tyrosine residues[4] (Figure 2) revealed that MAO active site is hydrophilic, but turns hydrophobic upon the substrate entrance that binds in the monocationic form. MAO selectivity has been investigated in the case of histamine, [5] which is not a physiological MAO substrate, yet is efficiently metabolized by MAO upon the N-methylation of the imidazole ring. Our results rationalized the MAO specificity with two substrates, histamine and N-methylhistamine, differing only in a single methyl group distant from the reactive centre. The insight gained through all these results led us to propose several promising strategies for preventing neurodegeneration.
Izvorni jezik
Engleski
Znanstvena područja
Kemija
POVEZANOST RADA
Projekti:
EK-334493 - Korištenje računalnih tehnika istraživanja biogenih amina u mozgu za liječenje neuroloških bolesti (COMPBAND) (Vianello, Robert, EK ) ( CroRIS)
Ustanove:
Institut "Ruđer Bošković", Zagreb
Profili:
Robert Vianello
(autor)